In states of illness, surgical operations and injuries, profound changes are induced in the energy and protein metabolism of the human body. This means, for example, loss of active cellular mass, leading to muscular fatigue, pronounced apathy and loss of appetite, and a period of convalescence involving general weakness which, for instance after a biliary tract operation, may last 5-6 weeks before the patient has regained his normal function. The cellular mass which is broken down very rapidly in different states of illness will need a time for re-establishment which is about four times as long as the time of breakdown for the same mass.
In critical states of illness and injuries, parenteral nutritional support is generally applied. In the past, preparations for intravenous nutritutional support generally contained an aqueous solution of a high caloric content carbohydrate, such as glucose and the like, fat and electrolytes. In prolonged states of illness or in injuries the nitrogen balance of the body must however be considered, i.e. the ratio of nitrogen loss to nitrogen intake. In the case of negative nitrogen balance, the parenteral nutritional support can be supplemented with amino acid supply to improve the nitrogen balance. Different amino acid compositions for parenteral supply are previously known, see e.g. SE Patent Application 8203965-2 and DE-A 25 30 246 concerning amino acid nutrient compositions in renal failure, WO 82/00411 concerning a nutrient composition containing branched-chain amino acids, and WO 83103969 concerning an aqueous nutrient solution consisting of L-amino acids.
From a survey made of the free amino acid pattern in the muscles, it has been found that skeletal muscle, which is the major body tissue in respect of weight, has a free amino acid pool, 62% of which consists of glutamine, see Bergstrom et al: Intracellular free amino acid concentration in human muscle tissue, J. of Appl. Physiol., Vol 36, No 6, 1874. In states of illness, injuries or surgical operations, this content decreases by 40-50%, see Vinnars et al: Influence of the postoperative state on the intracellular free amino acids in human muscle tissue. Annals of Surg., Vol 182, 6:665-671, 1975 and in states of blood poisoning, even more,.
It has been found that this glutamine reduction cannot be affected by enteral or parenteral nutritional support according to the methods hitherto available, see Vinnars et al: Metabolic effects of four intravenous nutritional regiments in patients undergoing elective surgery. II. Muscle amino acids and energy rich phosphates. Clin. Nutr. 2:3-11, 1983. There probably is a correlation between the inability immediately postoperatively to make a negative nitrogen balance positive and to normalise the exhausted intracellular glutamine pool and the reduced muscular mass and strength. This reduction probably depends on a reduced protein synthesis capacity post traumatically in skeletal muscle, see Werneman et al: Protein synthesis after trauma as studied by muscle ribosome profiles. Proceedings in the 7th ESPEN Congress. Ed. Dietze et al, Karger, Basel.
The addition to the nutritional support of a dipeptide of the type ornithine-alpha-ketogtutarate to a commercial amino acid solution has been found to improve to some extent, whereas not to normalise the intracellular glutamine pool, see Leander et al: Nitrogen sparing effect of Ornicetil in the immediate postoperative state. Clin. Nutr. 4:43-51, 1985. This preparation is however very expensive, and it has not been possible so far to evaluate whether its use in parenteral nutrition confers a clinical advantage.
When a patient is critically ill, it becomes necessary to resort to intravenous feeding. The nutrition substrates available for energy metabolism are various sugar solutions and fatty emulsions, which today seem appropriate. However, the amino acid solutions commercial available are inadequate, because they lack or have too low concentration of important amino acids such as tyrosine, cysteine, asparagine or glutamine. This is due to difficulties in heat-sterilising solutions of the amides, and also to the fact that the amides are unstable when stored. Another problem is that some of these compounds are relatively sparingly soluble and therefore require large amounts of water when being prepared.
After elective surgery, for instance biliary tract operations, it has been found that the negative nitrogen balance primarily depends on reduced protein synthesis which is assessed by determining the ribosome activity in skeletal muscle, see Wernerman et al: Protein synthesis in skeletal muscle after abdominal surgery: The effect of total parenteral nutrition. JPEN, 1985. An increased protein breakdown occurs only in very critical traumas and primarily in septic states. This reduced protein synthesis capacity cannot be affected by conventional intravenous or enteral nutritional support.
WO 89/03688 discloses that alpha-ketoglutarate has the same effect as glutamine when given to postoperative patients. Preliminary tests on patients subjected to a biliary tract operation showed that an addition of alpha-ketoglutarate to a conventional parenteral nutritional support program improves the nitrogen balance of the patients. Besides, the pathological amino acid changes which normally occur after injury or surgical operation are normalised and, also, the reduction of the ribosome activity is prevented.
Critically ill patients is a group of patients who are very ill. They have one or multiple organ failure, such as respiratory problem, renal, liver and/or intestinal insufficiency, a general protein catabolism and must be under intensive care. This group is different from the group of postoperative patients, who often has normal glutamine and protein values before the operation and for who the drop in glutamine level is due to the operation. Critically ill patients have a pronounced protein catabolism and a lower skeletal glutamine content than postoperative patients.
Critically ill patients have a decrease of at least 50% of the normal glutamine concentration in skeletal muscle. In extreme cases there is a drop to 70-80%. Roth et al (Clin Nutr 1:25-42, 1982) have shown that there is correlation of mortality of the patients with a decrease of more than 70%.
Jeppson et al (Am J Physiol 1988, 255, E166-172) has shown a correlation between the protein synthesis and glutamine level in skeletal muscle. By improving the glutamine level in skeletal muscle the protein synthesis capacity is improved and the lean body mass is preserved. This correlation is of importance for the interpretation of the results given in the example below.
Earlier studies (J. Karner and E. Roth, Clin Nutr. Vol 9, 1990, 43-44) have shown that when alanylo-glutamine is given in an amount of 20 g/day per patient to two patients, no influence on the skeletal muscle of critically ill patients could be established and when 40 g/day per patient was given to two patients, a marginal improvement of the muscle glutamine concentration could be seen. When 60 g/day was given to two patients an improvement of 50-100% was found.
It is also of importance to maintain the energy status in the skeletal muscle tissue for critical ill patients. The energy status is coupled to the protein synthesis, but the mechanism is not totally known.